KR20090010071A - 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazepine, methods and preparations thereof, and compositions containing the same - Google Patents

Abstract

The present invention relates in particular to 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazine of formula (I), to a process for the preparation thereof, to compositions containing them, and to their use as medicines, in particular as anticancer agents.

<Formula I>

Description

2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazine, preparation method and use thereof, and composition containing same {2-ALKOXY-3,4,5-TRIHYDROXY-ALKYLAMIDE-BENZAZEPINES, THE PREPARATION AND USE THEREOF, AND COMPOSITIONS CONTAINING THE SAME}

The present invention relates in particular to 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazine, methods for their preparation, compositions containing them, and their use as medicaments.

More specifically, according to the first aspect, the present invention relates to 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazine which can be used as an anticancer agent.

2-methoxy-3,4,5-trihydroxyalkylamides are described in US 6239127, US 20010044433 A1, WO 01/85697, WO 00/29382, US 4831135, EP 687673 and US 2002128474 A1. These documents disclose essentially analogs and derivatives of bengamide, a natural product isolated from the spongy animal Jaspis coriacea .

The same product as described above is described in J. Org. Chem. (1986), 51 (23), 4494-7; [J. Org. Chem. (2001), 66 (5), 1733-41; [J. Med. Chem. 2001, 44, 3692-9.

The problem to be solved by the present invention is to obtain a novel product having anticancer activity. In addition to maintaining anticancer activity, some of these novel products may also have advantageous properties with regard to their pharmacological activity such as their pharmacokinetics, bioavailability, solubility, stability, toxicity, absorption and metabolism.

One subject of the invention is a product corresponding to formula (I).

In the formula:

a) R ₁ is independently (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl (C ₁ -C ₁₂ ) alkyl, cycloalkyl (C ₂ -C ₁₂ ) alkenyl, cycloalkyl (C ₂ -C ₁₂ ) alkynyl, heterocyclyl (C ₁ -C ₁₂ ) alkyl, heterocyclyl (C ₂ -C ₁₂ ) alkenyl, heterocyclyl (C ₂ -C ₁₂ ) alkynyl, aryl (C ₁ -C ₁₂ ) alkyl, aryl (C ₂ -C ₁₂ ) alkenyl, aryl (C ₂ -C ₁₂ ) Alkynyl, heteroaryl (C ₁ -C ₁₂ ) alkyl, heteroaryl (C ₂ -C ₁₂ ) alkenyl, heteroaryl (C ₂ -C ₁₂ ) alkynyl, each of R ₁ aryl The group is optionally substituted with one or more halogens;

b) R ₂ is (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkylthio ( C ₁ -C ₆ ) alkyl, di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, aryloxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C _1- C ₆ ) alkyl;

c) R ₃ is selected from the group consisting of H, COO (R ₅ ), CONH (R ₅ ), CO (R ₅ ), O (R ₅ ) and R ₅ ;

d) R ₄ is independently F, Cl, Br, N (R ₅ ) ₂ , NO ₂ , CN, COO (R ₅ ), CON (R ₅ ) ₂ , NHCO (R ₅ ), NHCOO (R ₅ ), OCONH (R ₅ ), O (R ₅ ) and R ₅ or two substituents R ₄ attached to two adjacent carbons of phenyl together are selected from cycloalkyl, heterocyclyl, aryl or heteroaryl Forming a ring, which is optionally substituted with one or more R ₄ ;

e) m has a value of 0, 1, 2, 3 or 4;

f) R ₅ is independently a pair of non-bonding electrons, H, (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, halo (C ₁ -C ₁₂ ) alkyl, aryl (C ₁ -C ₁₂ ) alkyl, heteroaryl (C ₁ -C ₁₂ ) alkyl, heteroarylaryl (C ₁ -C ₁₂ ) alkyl, aryl, heteroaryl and cycloalkyl, Wherein each R ₅ is OH, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, aryl (C ₁ -C ₄ ) alkyl, aryl, heteroaryl (C ₁ -C ₄ ) alkyl , Heteroaryl, -N (CH ₃ ) ₂ , -NH ₂ , CONH ₂ ,

에서 선택되는 1개 이상의 치환기로 임의로 치환되고, 각각의 Rz는 독립적으로 H, COO(R₅), CONH(R₅), CON(R₅)₂, CO(R₅) 및 R₅로 이루어진 군에서 선택되며, 여기서 각각의 R₅는 독립적으로 (C₁-C₄)알킬, 할로(C₁-C₄)알킬, 아릴(C₁-C₄)알킬 및 헤테로아릴(C₁-C₄)알킬에서 선택되고, 여기서 각각의 R₅는 OH, 할로겐, (C₁-C₄)알킬, (C₁-C₄)알콕시, 아릴(C₁-C₄)알킬, 아릴, 헤테로아릴(C₁-C₄)알킬 및 헤테로아릴에서 선택되는 치환기로 임의로 치환되고;

Optionally substituted with one or more substituents selected from, each Rz is, independently, a group consisting of H, COO (R ₅ ), CONH (R ₅ ), CON (R ₅ ) ₂ , CO (R ₅ ) and R ₅ Wherein each R ₅ is independently (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₄ ) alkyl, aryl (C ₁ -C ₄ ) alkyl and heteroaryl (C ₁ -C ₄ ) Alkyl, wherein each R ₅ is OH, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, aryl (C ₁ -C ₄ ) alkyl, aryl, heteroaryl (C ₁ -C ₄ ) optionally substituted with a substituent selected from alkyl and heteroaryl;

Provided that when R ₁ is (E) -CH = CH-C (CH ₃ ) ₃ , R ₂ is methyl and R ₃ is H, m is not zero.

One subject of the invention is that R ₁ independently represents (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, aryl (C ₁ -C ₁₂ ) alkyl, aryl (C ₂ -C ₁₂ ) alkenyl, aryl (C ₂ -C ₁₂ ) alkynyl, heteroaryl (C ₁ -C ₁₂ ) alkyl, heteroaryl (C ₂ -C ₁₂ ) alkenyl and heteroaryl (C ₂ -C ₁₂ ) alkynyl.

One subject of the invention is that R ₂ is (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, (C ₂ -C ₁₂ ) Alkenylaryl, (C ₂ -C ₁₂ ) alkenylheteroaryl, (C ₁ -C ₆ ) alkylthio (C ₁ -C ₆ ) alkyl, di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl and aryloxy (C ₁ -C ₆ ) alkyl are products of formula (I) above selected from the group consisting of:

According to the invention, R ₁ is preferably selected from -C (R ₆ ) = C (R ₇ ) (R ₈ ), wherein R ₆ , R ₇ and R ₈ are independently H, (C ₁ -C) ₆ ) alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

More preferably, R ₁ is (E) -CH = CH-CH (CH ₃ ) (C ₂ H ₅ ), (E) -CH = CH-CH (CH ₃ ) ₂ and (E) -CH = CH -C (CH ₃ ) ₃ or (E) -C (CH ₃ ) = CH-CH (CH ₃ ) (C ₂ H ₅ ), (E) -C (CH ₃ ) = CH-CH (CH ₃ ) ₂ and (E) -C (CH ₃ ) = CH-C (CH ₃ ) ₃ .

More preferably, R ₁ is selected from (E) —CH═CH—C ₅ H ₉ .

According to the invention, R ₂ is preferably methyl.

Among the subject matter of the present invention, the first group is characterized in that R ₃ is independently selected from methyl group or (3,5-difluorophenyl) methyl group. The second group is characterized in that R ₃ is H.

Among the subject matter of the present invention, the third group is characterized in that R ₄ is independently selected from F, Cl, Br, phenyl and pyridinyl. The fourth group is characterized in that m is zero.

Preferably, the present invention relates to the products illustrated in Table 1.

According to another aspect, the invention relates to a process for the preparation of the product of formula (I) or (I '). The product of formula (I ') is an optically active precursor of the product of formula (I). The product of formula (I) is obtained from the product of formula (I ') by the methods described or by one or more reactions customary to those skilled in the art, for example cyclopropaneation, oxidation or chiral separation.

The product of formula (I) or (I ') can be obtained by hydrolysis of the product of formula (II).

Wherein R ₁ , R ₂ , R ₃ , R ₄ and m are as defined above.

The product of formula (II) can be obtained by reaction of the product of formula (III) with the product of formula (IV).

Wherein R ₃ , R ₄ and m are as defined above.

Wherein R ₁ and R ₂ are as defined above.

The product of formula (I) or (I ') can also be obtained by reaction of the product of formula (III) with the product of formula (V) as described above.

Wherein R ₁ and R ₂ are as defined above.

The product of formula V can be obtained by hydrolysis of the product of formula IV.

<Formula IV>

Wherein R ₁ and R ₂ are as defined above.

The product of formula (V) wherein R ₁ is -CH = CH-R ' ₁ can also be obtained by hydrolyzing the product of formula (VII) to yield the product of formula (VI), which is metathesized to yield the product of formula (V).

Wherein R ₂ is as defined above.

Wherein R ₂ is as defined above.

<Formula V>

Wherein R ₁ is —CH═CH—R ′ ₁ and R ′ ₁ is a (C ₁ -C ₆ ) alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

The product of formula VII can be obtained by double dehydration of the product of VIII.

Wherein R ₂ is as defined above.

The product of formula I 'or II as defined above except that R ₁ is (E) -CH = CH-C (CH ₃ ) ₃ , R ₂ is methyl, R ₃ is H and m is 0 Is one subject of the present invention.

R ₃ is H, methyl or (3,5-difluorophenyl) methyl, and R ₄ is bromine atom or phenyl or m is 0 except that R ₃ is H and m has a value of 0 The product of formula III having a is one subject of the invention.

Products of Formulas IV and V wherein R ₂ is methyl and R ₁ is-(E) -CH = CH-C ₅ H ₉ are the subject of the present invention.

The product of formula VI wherein R ₂ is methyl is one subject of the invention. The product of formula (VII) wherein R ₂ is methyl is one subject of the invention.

The products according to the invention may exist in the form of bases, addition salts with acids, solvates, hydrates or prodrugs.

The product according to the invention can be in non-chiral form or racemic form, or in one stereoisomeric-rich form or in one enantiomer-rich form; Optionally chloride. Preferred are products in which the carbon attached to the exocyclic amine is in the (S) configuration.

The product according to the invention can be used for the manufacture of a medicament which can be used to prevent or treat pathological conditions, in particular cancer.

The products of the present invention are also useful for pathological conditions in which neovascularization or angiogenesis occurs in an inappropriate manner, namely general cancers, and certain cancers such as Kaposi's sarcoma or infant angioma, as well as rheumatoid arthritis, osteoarthritis and / or related pain, inflammatory It can be used for the manufacture of a medicament that can be used to prevent or treat intestinal diseases such as ulcerative colitis or Crohn's disease, eye pathological conditions such as age-related macular degeneration or diabetic retinopathy, chronic inflammation and psoriasis.

Angiogenesis is the process by which new capillaries develop from existing blood vessels. Tumor neovascularization (formation of new blood vessels), which is essential for tumor growth, is also one of the essential factors of metastasis (Oncogene. 2003 May 19; 22 (20): 3172-9; Nat Med. 1995 Jan; 1 (1): 27- 31).

The invention also relates to a therapeutic composition containing a compound according to the invention with a pharmaceutically acceptable excipient according to the chosen method of administration. The pharmaceutical composition may be in solid or liquid form, or in liposome form.

Among the solid compositions, mention may be made of powders, gelatin capsules and tablets. Among the oral forms, solid forms protected against the acidic medium of the stomach may also be included. The supports used in the solid form consist in particular of inorganic supports such as phosphates or carbonates, or of organic supports such as lactose, cellulose, starch or polymers. The liquid form consists of a solution, suspension or dispersion. They contain water or organic solvents (ethanol, NMP, etc.), or mixtures of surfactants and solvents, or mixtures of complexing agents and solvents as dispersible supports.

The liquid form will preferably be injectable and therefore will have an acceptable formulation for this use.

Routes acceptable for administration by injection include the intravenous, intraperitoneal, intramuscular and subcutaneous routes, with the intravenous route being preferred.

The dosage of the compound of the present invention will be suitably adjusted by the attending physician according to the route of administration to the patient and the condition of the patient.

The compounds of the present invention can be administered alone or as a mixture with other anticancer agents. Among the possible combinations, mention may be made of:

Alkylating agents, in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednismustine, carmustine, lomustine, semustine, streptozotocin, decarbazine, temozolomide , Procarbazine and hexamethylmelamine;

Platinum derivatives such as especially cisplatin, carboplatin or oxaliplatin;

Antibiotics such as bleomycin, mitomycin or dactinomycin;

Antimicrotubules such as in particular vinblastine, vincristine, vindesine, vinorelbine or taxoids (paclitaxel and docetaxel);

Anthracyclines, such as in particular doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone or roxanthrone;

Group 1 and Group 2 topoisomerases such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex;

Fluoropyrimidines such as 5-fluorouracil, UFT or phloxuridine;

Cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptopurine and 6-thioguanine;

Adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate;

Methotrexate and folic acid;

Various enzymes and compounds, such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramines, dexarazonic acid, amifostine, herceptin, and estrogen and androgen hormones;

Anti-angiogenic agents such as combretastatin derivatives such as CA4P, chalcone or colchicine such as ZD6126, and prodrugs thereof;

Kinase inhibitors such as ertonitrile or imatinib;

Biotherapeutics such as antibodies such as rituximab, bevacizumab, cetuximab, trastuzumab or alemtuzumab;

Proteosome inhibitors, such as bortezomib.

It is also possible to use the compounds of the present invention in combination with radiation therapy. These treatments can be performed simultaneously, separately or sequentially. The treatment will be adjusted appropriately by the attending physician depending on the patient to be treated.

Justice

The term "halogen" refers to an element selected from F, Cl, Br and I.

The term "alkyl" refers to a linear or branched saturated hydrocarbon-based substituent containing 1 to 12 carbon atoms. Methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1 -Dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3,3- Dimethylbutyl, heptyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl and dodecyl substituents are examples of alkyl substituents.

The term "alkenyl" refers to a linear or branched hydrocarbon-based substituent having at least one unsaturation and containing 2 to 12 carbon atoms. Ethylenyl, 1-methylethylenyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-1-enyl, Z-1 , 2-dimethylprop-1-enyl, E-1,2-dimethylprop-1-enyl, but-1,3-dienyl, 1-methylidedenylprop-2-enyl, Z-2- Methylbut-1,3-dienyl, E-2-methylbut-1,3-dienyl, 2-methyl-1-methylidedenylprop-2-enyl, undec-1-enyl and undec- 10-enyl substituents are examples of alkenyl substituents.

The term "alkynyl" refers to a linear or branched hydrocarbon-based substituent having two or more unsaturations produced by adjacent pairs of carbon atoms and containing 2 to 12 carbon atoms. Ethynyl, prop-1-ynyl, prop-2-ynyl and but-1-ynyl substituents are examples of alkynyl substituents.

The term "aryl" refers to monocyclic or polycyclic aromatic substituents containing 6 to 14 carbon atoms. Phenyl, naphth-1-yl, naphth-2-yl, anthracene-9-yl, 1,2,3,4-tetrahydronaphth-5-yl and 1,2,3,4-tetrahydrona A ft-6-yl substituent is an example of an aryl substituent.

The term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic substituent containing 1 to 13 carbon atoms and 1 to 4 heteroatoms. Pyrrole-1-yl; Pyrrole-2-yl; Pyrrole-3-yl; Furyl; Thienyl; Imidazolyl; Oxazolyl; Thiazolyl; 2 soxazolyl; Isothiazolyl; 1,2,4-triazolyl; Oxdiazolyl; Thiadiazolyl; Tetrazolyl; Pyridyl; Pyrimidyl; Pyrazinyl; 1,3,5-triazinyl; Indolyl; Benzo [b] furyl; Benzo [b] thienyl; Indazolyl; Benzimidazolyl; Azaindoleyl; Quinoleyl; Isoquinoleyl; Carbazolyl and acridil substituents are examples of heteroaryl substituents.

The term "heteroatom" refers herein to a bivalent or higher atom that is not carbon. N; O; S and Se are examples of heteroatoms.

The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon-based substituent containing 3 to 12 carbon atoms. Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo [2.2.1] heptyl, cyclooctyl, bicyclo [2.2.2] octyl, acyl Danmantyl and perhydronaphthyl substituents are examples of cycloalkyl substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon-based substituent containing 1 to 13 carbon atoms and 1 to 4 heteroatoms. Preferably, saturated or partially unsaturated cyclic hydrocarbon based substituents will be monocyclic and contain 4 or 5 carbon atoms and 1 to 3 heteroatoms.

With respect to the term “condensed phenyl”, when m has a value of 0 it means that it is a non-substituted phenyl (or phenyl substituted with 4 hydrogen atoms) and m has a value of 1, 2, 3 or 4 In this case 1, 2, 3 or 4 hydrogen atoms are substituted with a substituent R ₄ .

The advantages of the invention will be explained in more detail by the following examples.

Abbreviation:

Ac acetate; Bn benzyl; ℃ Celsius degree; cat . catalyst; TLC thin layer chromatography; PCC preparative column chromatography; cm centimeters; δ chemical shift; d doublet; dd Doublet of doublets; DMF Dimethylformamide; DMSO - d ⁶ Deuterated Dimethyl Sulfoxide; doublet of dt triplets; eq . equivalent weight; ES +/- electrospray (positive / voice mode); Et ethyl; g gram; h hour; Hz hertz; 50% inhibition constant of IC ₅₀ activity; iPr isopropyl; d day; J coupling constants; Liquid chromatography coupled to an LCMS mass spectrometer; m multiplet; Me methyl; mg milligrams; MHz megahertz; ml milliliters; Μl microliters; mm millimeters; Micron micrometer; mmol millimoles; min minutes; N mol. L ^-1 ; Mp melting point; Ph phenyl; ppm parts per million; q quartet; Yld yield; Rf front ratio; ¹ H NMR proton nuclear magnetic resonance; s singlet; bs broadband singlet; t triplet; AT ambient temperature; tBu tert-butyl; TFA trifluoroacetic acid; THF tetrahydrofuran; t _R retention time; UV ultraviolet light; V bolts.

Ex1 : N- [1- (3,5-difluorobenzyl) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E) -(2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide

Step 1: Preparation of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl) carbamate ( 2 )

A solution of 2.48 g (11.4 mmol) of tBoc ₂ O in 50 ml of CHCl ₃ was added at 0 ° C. and 1 2.0 g (11.4 mmol) (3-amino-1,3,4,5-tetrahydro-2H-1-benzase Pin-2-one, commercially available from Interchim), was added to a 250 ml round bottom flask containing 1.15 ml (11.4 mmol) of TEA and 50 ml of CHCl ₃ . The medium was stirred under argon at 0 ° C. for 2 h. The reaction medium was washed with 10 ml HCl (IN) and 100 ml water. The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness. 3.75 g of a cream solid were obtained, which were triturated in 20 ml of isopropyl ether. Filter-after drying, 2 2.3 g (grey-white solid) were obtained.

Step 2: tert-butyl [1- (3,5-difluorobenzyl) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate ( 3 )

72 mg (1.81 mmol) of sodium hydride in a 60% suspension in oil were introduced in an AT under an argon atmosphere with stirring to a 100 ml round bottom flask containing 20 ml THF and 2 0.5 g (1.81 mmol). The medium was stirred for 1 h, then 0.75 g (3.62 mmol) of 3,5-difluorobenzyl bromide were added. The medium was stirred overnight at AT. 50 ml of EtOAc were added and the organic phase was washed with 50 ml of water. The organic phase was dried over MgSO ₄ , filtered and then evaporated to dryness. 1 g of a white solid was obtained. After trituration with 20 ml of isopropyl ether and filter-drying, 0.62 g of product 3 (white solid) was obtained.

Step 3: Preparation of hydrochloride ( 4 ) of 3-amino-1- (3,5-difluorobenzyl) -1,3,4,5-tetrahydro-1-benzazin-2-one

3 0.62 g (1.54 mmol) was dissolved in a 25 ml round bottom flask and 10 ml of a solution of hydrochloric acid (4 M) in dioxane were added. The medium was stirred under argon at AT for 5 h. After evaporating off the solvent, amine 4 in the form of hydrochloride 0.46 g was obtained and used directly in the next step.

Step 4: N- [1- (3,5-Difluorobenzyl) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] -2- [ (4R, 5S, 6R) -6-((E) -3,3-dimethylbut-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxynan-4-yl] Preparation of 2-methoxyacetamide ( 6 )

5 in 2 ml of THF 100 mg (352 μmol) (can be prepared according to the procedure described in Org. Process Res. Dev. 2003, 7 (6), 856-865), 4 239 mg (0.70 mmol) and sodium 2-ethyl 146 mg (0.77 mmol) of hexanoate were introduced into Wheaton tubes continuously under an argon atmosphere with stirring. Stirring was maintained at AT for 24 h. 3 ml of ethyl acetate was added to the reaction medium. The mixture was washed successively with 3 ml of a solution of HCl (IN) followed by 3 ml of a saturated solution of NaHCO ₃ and 3 ml of water. The organic phase was dried over anhydrous magnesium sulfate, filtered and then evaporated to dryness. 450 mg of a colorless oil was obtained, which was chromatographed on a silica cartridge (20 g, eluent CH ₂ Cl ₂ / MeOH-1 to 10% MeOH gradient). 122 mg of expected product 6 was recovered.

Step 5: N- [1- (3,5-Difluorobenzyl) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E Preparation of)-(2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide ( Ex1 )

6 92 mg (157 μmol) in 0.8 ml THF and 1.57 ml (1.57 mmol) of 1 N hydrochloric acid were mixed under argon with stirring in a 10 ml round bottom flask. Stirring was maintained at AT for 5 h. A precipitate formed, which was filter-dried on a sintered glass funnel. 0.5 ml of THF, followed by 2 ml of isopropyl ether and dried in vacuo, followed by Ex1 70 mg (white solid) were obtained.

Ex2 : N- [1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E)-(2R, 3R, 4S, 5R) ) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide

Step 1: Preparation of tert-butyl [1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate ( 7 )

174 mg (4.34 mmol) of sodium hydride in a 60% suspension in oil were introduced under AT into an 100 ml round bottom flask containing 50 ml THF and 2 1.2 g (4.34 mmol) at AT. The medium was stirred for 1 h and then 1.23 g (8.69 mmol) of methyl iodide were added. The medium is stirred overnight, 50 ml of EtOAc are added and the organic phase is washed with 100 ml of water. The organic phase was dried over MgSO ₄ , filtered and then evaporated to dryness. 1.3 g of a white solid were obtained. After chromatography on a silica cartridge (40 g) (with eluent CH ₂ Cl ₂ / MeOH-1 to 10% MeOH gradient), 0.66 g of product 7 (white solid) was obtained.

Step 2: Preparation of hydrochloride ( 8 ) of 3-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazin-2-one

7 0.66 g (2.27 mmol) was dissolved in a 50 ml round bottom flask and 15 ml of a solution of hydrochloric acid in dioxane (4 M) was added. The mixture was stirred under argon at AT for 5 h. After evaporating off the solvent, amine 8 in the form of hydrochloride 0.53 g was obtained and used directly in the next step.

Step 3: (3R, 4R, 5S) -4-hydroxy-5-((E)-(R) -1-hydroxy-4,4-dimethylpent-2-enyl) -3-methoxydihydrofuran Preparation of 2-one ( 9 )

17 ml of TFA in 10 ml of water was added to a 250 ml round bottom flask containing 3 3.6 g of suspension and 40 ml of water. The medium was stirred at AT for 1.5 h. The medium was diluted with 290 ml of water, frozen and lyophilized. 4 g of oil were obtained, which was crystallized from 20 ml of isopropyl ether at AT. After filter-drying, washing with isopropyl ether and vacuum drying at 40 ° C., 2.46 g of expected product 7 (white crystals) was obtained.

Step 4: N- [1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E)-(2R, 3R, 4S, Preparation of 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide ( Ex2 )

9 in 1.0 ml of THF 36 mg (147 μmol), 8 66.8 mg (0.30 mmol), 61 mg (0.37 mmol) of sodium 2-ethylhexanoate were introduced into the Wheaton tube continuously under argon atmosphere with stirring. Stirring was maintained at AT for 24 h. The reaction medium was directly evaporated to dryness. The crude material was chromatographed on a silica cartridge (5 g, eluent CH ₂ Cl ₂ / MeOH-1 to 10% MeOH gradient). Expected product Ex2 39 mg was recovered.

ES: m / z = 457 MNa ⁺ ; m / z = 435 MH ⁺ .

Ex3 : N- (7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S, 5R ) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide and Ex3a & Ex3b

Step 1: Preparation of tert-butyl (7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl) carbamate ( 10 )

472 mg (2.65 mmol) of N-bromosuccinimide were introduced at AT into an 100 ml round bottom flask containing 40 ml EtOAc and 2 0.5 g (1.8 mmol) under argon atmosphere. The medium was stirred overnight and washed with 40 ml of HCl (IN), 40 ml of a saturated aqueous solution of NaHCO ₃ and 40 ml of water. The organic phase was dried over MgSO ₄ , filtered and then evaporated to dryness. 1.3 g of oil were obtained, which was crystallized from 10 ml of isopropyl ether. After filter-drying, 450 mg of product 10 (white solid) was obtained.

Step 2: Preparation of Hydrochloride ( 11 ) of 3-Amino-7-bromo-1,3,4,5-tetrahydro-1-benzazin-2-one

10 0.45 g (1.27 mmol) was dissolved in a 25 ml round bottom flask and 10 ml of a solution of hydrochloric acid (4 M) in dioxane were added. The medium was stirred under argon at AT for 5 h. A precipitate formed, which was filtered on a sintered glass funnel and washed with 5 ml of dioxane followed by 5 ml of isopropyl ether. Amine in Hydrochloride Form 11 0.38 g was obtained.

Step 3: (R) -N- (7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl) -2-[(4R, 5S , 6R) -6-((E) -3,3-dimethylbut-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxynan-4-yl] -2-meth Preparation of oxyacetamide ( 12 )

5 in 2 ml of THF 100 mg (352 μmol), 11 205 mg (0.70 mmol) and 146 mg (0.77 mmol) sodium 2-ethylhexanoate were introduced into the Wheaton tube continuously under argon atmosphere with stirring. Stirring was maintained at AT for 24 h. The medium was evaporated to dryness and then purified by chromatography on a silica cartridge (20 g) using an eluent of CH ₂ Cl ₂ / MeOH (with a gradient of 1 → 10% MeOH). Expected product 12 160 mg was recovered.

Step 4: N- (7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S, Preparation of 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide ( Ex3 ) and Ex3a & Ex3b

150 mg (258 μmol) 12 in 1.4 ml THF and 2.78 ml 1 N hydrochloric acid were introduced into a 25 ml round bottom flask under argon with stirring. Stirring was maintained at AT for 4.5 h. The medium was neutralized with NaOH (IN) to pH 7 and extracted twice with 3 ml EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was chromatographed on silica cartridge (10 g) with elution using CH ₂ Cl ₂ / MeOH (with a gradient of 1 → 10% MeOH). 65 mg of the expected product Ex3 was recovered. The Ex3 40 mg was purified by preparative chiral HPLC (Kira pad (Chirapad) AD-H 5 μm 250 × 4.6 mm, flow rate 1 ml / min, mobile phase: 50% heptane -50% EtOH, 0.1% TEA) to remove by Ex3a 9 mg (tr = 7.48 min) and Ex3b 20 mg (tr = 9.71 min) were provided.

Ex4 : N- (7-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide and Ex4a & Ex4b

Step 1: Preparation of tert-butyl (7-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl) carbamate ( 13 )

371 mg (3.04 mmol) of phenylboronic acid, 62 mg of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (C ₃₅ H ₃₀ Cl ₄ FeP ₂ Pd, Mw 816.65, 0.025 mmol) and 3.96 g of cesium carbonate ( 12.16 mmol) was introduced under argon atmosphere with stirring into a 100 ml round bottom flask containing 22 ml of water, 6.5 ml of dioxane and 10 1.08 g (3.04 mmol). The medium was heated at 100 ° C. for 1 h with stirring. The medium was filtered over celite and washed with 10 ml dioxane, 10 ml CH ₂ Cl _{2 and} 10 ml MeOH. The filtrate was concentrated in vacuo. Then 25 ml of EtOAc were added and the mixture was washed twice with 25 ml of water. The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was chromatographed on silica cartridge (50 g) with elution using CH ₂ Cl ₂ / MeOH (MeOH gradient: 1 → 10%). 350 mg of the expected product 13 (white solid) was recovered.

Step 2: Preparation of Hydrochloride 14 of 3-Amino-7-phenyl-1,3,4,5-tetrahydro-1-benzazin-2-one

13 0.35 g (0.99 mmol) was dissolved in a 20 ml round bottom flask and 5 ml of a solution of hydrochloric acid (4 M) in dioxane were added. The medium was stirred under argon at AT for 5 h. A precipitate formed which was filter-dried and washed with 5 ml of dioxane followed by 5 ml of isopropyl ether. After drying, amine 14 in hydrochloride form 0.23 g was obtained.

Step 3: (R) -N- (7-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl) -2-[(4R, 5S, 6R) -6-((E) -3,3-dimethylbut-1-enyl) -5-hydroxy-2,2-dimethyl-1,3-dioxynan-4-yl] -2-methoxy Preparation of acetamide ( 15 )

5 100 mg (352 μmol), 14 203 mg (0.70 mmol) and 146 mg (0.77 mmol) sodium 2-ethylhexanoate in 2 ml of THF were introduced into the Wheaton tube continuously under argon atmosphere with stirring. Stirring was maintained at AT for 24 h. The mixture was evaporated to dryness and then purified by chromatography on silica cartridge (20 g) with elution using CH ₂ Cl ₂ / MeOH (MeOH gradient: 1 → 10%). 150 mg of expected product 15 was recovered.

Step 4: N- (7-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S, 5R Preparation of) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide ( Ex4 ) and Ex4a & Ex4b

15 150 mg (280 μmol) in 1.4 ml of THF and 2.78 ml of 1 N hydrochloric acid were introduced into a 20 ml round bottom flask under argon with stirring. Stirring was maintained at AT for 4 h. The medium was neutralized with NaOH (IN) to pH 7 and extracted twice with 5 ml of EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was chromatographed on silica cartridge (10 g) using an eluent of CH ₂ Cl ₂ / MeOH (with a gradient of 1 → 10% MeOH). 85 mg of the expected product Ex4 was recovered. 58 mg of Ex4 were separated by preparative chiral HPLC (Kirapad AD-H 5 μm 250 × 4.6 mm, flow rate 1 ml / min, mobile phase: 70% heptane-30% EtOH, 0.1% TEA) to obtain Ex4a 16 mg (tr = 13.42 min) and Ex4b 40 mg (tr = 18.96 min).

Ex4a : (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S) -2-oxo-7-phenyl- 2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] non-6-enamide

Step 1: Preparation of tert-butyl [(3S) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate ( 2a )

A solution of 24.77 g (113.5 mmol) of tBoc ₂ O in 16 ml (113.5 mmol) of TEA and 500 ml of CHCl ₃ was added at 0 ° C., 1a 20.0 g (113.5 mmol) ((s) -3-amino-1,3, 4,5-tetrahydro-2H-1-benzazin-2-one, prepared according to the procedure described in J. Org. Chem. 1997, 62, 8271) and 500 ml of CHCl ₃ It was added to a 2 L round bottom flask. The medium was stirred overnight. The reaction medium was washed with 500 ml of HCl (0.5 N) and 500 ml of water. The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness and the solid was broken down with 200 ml of isopropyl ether. After filter-drying, 2a 30.02 g (grey-white solid) were obtained.

Step 2: tert-butyl [(3S) -7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate ( 10a ) Produce

23.5 g (136 mmol) of N-bromosuccinimide in 4-part over 3 days in a 2 L three-necked flask containing 1.5 L EtOAc and 1.5 g 2a 8.47 g (103.0 mmol) at AT, under argon atmosphere with stirring Introduced. The medium was further stirred overnight and washed with 500 ml of HCl (0.5 N), 500 ml of saturated aqueous solution of NaHCO ₃ and 500 ml of water. The organic phase was dried over MgSO ₄ , filtered and then evaporated to dryness. 38 g of brown foam were obtained. The product was purified by chromatography on silica cartridge (600 g) with elution using heptane / EtOAc (70/30). 20.46 g of the expected product 10a (white solid) was recovered.

Step 3: tert-Butyl [(3S) -2-oxo-7-phenyl-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate Preparation of ( 13a )

Phenylboronic acid 2.643 g (21.68 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride 402 mg (C ₃₅ H ₃₀ Cl ₄ FeP ₂ Pd, Mw 816.65, 0.493 mmol) and cesium carbonate 25.69 g ( 78.84 mmol) was introduced under argon atmosphere with stirring into a 500 ml round bottom flask containing 142 ml of water, 42 ml of dioxane and 7.0 g (19.71 mmol) of 10a . The medium was heated at 100 ° C. for 4 h with stirring. Dioxane was concentrated in vacuo, 100 ml of distilled water were added and the mixture was extracted with 2 × 200 ml of EtOAc. The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness. 7 g of a brown solid were obtained, which crystallized from 55 ml of toluene under high temperature conditions. After the product was left overnight at AT, the needles were filter-dried and washed with 5 ml of toluene and 5 ml of isopropyl ether. After vacuum drying, 5.63 g of expected product 13a was obtained.

Step 3: Preparation of (3S) -3-amino-7-phenyl-1,3,4,5-tetrahydro-2H-1-benzazin-2-one hydrochloride ( 14a )

5.63 g (15.97 mmol) of 13a were dissolved in a 250 ml round bottom flask and 140 ml of a solution of hydrochloric acid in dioxane (4 M) was added. The medium was stirred under argon at AT for 4 h. A precipitate formed which was filter-dried and washed with 5 ml of dioxane followed by 5 ml of isopropyl ether. After vacuum drying, amine 14a in hydrochloride form 5.7 g was obtained.

Step 4: (2R, 3R, 4S, 5R, 6E) -3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S) -2-oxo-7-phenyl -2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] non-6-enamide Preparation of ( Ex4a )

9 2.3 g (9.42 mmol), 14a 2.72 g (9.42 mmol) and 3.63 g (21.84 mmol) sodium 2-ethylhexanoate in 50.0 ml of THF were introduced into a continuous 150 ml round bottom flask under an argon atmosphere with stirring. Stirring was maintained at AT for 48 h. The reaction medium was directly evaporated to dryness. The crude material was chromatographed on a silica cartridge (300 g, eluent EtOAc) to give 3.7 g of a white solid, which was purified by silica cartridge (240 g, eluent CH ₂ Cl ₂ / MeOH-MeOH gradient: 1 → 5%). ). Expected product Ex4a 3.23 g of (white solid) was recovered.

Ex5 : (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N-[(3S) -2-oxo-7-phenyl-2 , 3,4,5-tetrahydro-1H-1-benzazin-3-yl] hept-6-enamide

Step 1: (4R, 4aS, 7R, 7aR) -7-methoxy-2,2-dimethyl-4-vinyl-tetrahydro-6H-furo [3,2-d] [1,3] dioxine-6 Preparation of on-ion ( 17 )

A 4000 ml round bottom flask equipped with a magnetic stirrer was charged with 178.2 g (0.679 mol) of PPh ₃ , 84.1 g (1.235 mol) of imidazole and 2430 ml of dry THF under nitrogen. 156.8 g (0.618 mol) of sublimed iodine in duplicate were carefully added while maintaining the temperature of the reaction mixture at 30 ° C. This medium can be refluxed for 1 h (66 ° C.) and then prepared according to the procedure described in 16 81 g (0.309 mol) (Org. Process Res. Dev. 2003, 7 (6), 856-865). ) Was added little by little at 66 ° C +/- 2 ° C. The homogeneous mixture thus obtained was refluxed for 3 h. After returning to 20 ° C. + / − 5 ° C., 1000 ml of 10% NaHCO ₃ solution (boiling, non-thermal conductivity) (pH 8.0-8.5) was added. 185.5 g of Na ₂ S ₂ O ₃ were then added until almost complete discoloration was obtained (appearance of inorganic precipitates). After 30 min stirring at 20 ° C +/- 5 ° C, the solids were filtered off and rinsed with THF. The THF / H ₂ O filtrate was partially concentrated in a rotary evaporator at a temperature below 35 ° C. The aqueous concentrate was saturated with NaCl and extracted with 1500 ml of CH ₂ Cl ₂ . The organic phase was dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up in 2000 ml of a mixture of H ₂ O / acetone (75/25) and the insoluble material was filtered off and rinsed with a mixture of H ₂ O / acetone (75/25). The filtrate was concentrated in a rotary evaporator at 50 ° C. and 20 mbar and filtered again on a sintered glass funnel (porosity No. 4). The aqueous phase was saturated with NaCl and extracted three times (1000 ml, 500 ml and 250 ml) with CH ₂ Cl ₂ . The organic phases were combined, dried over MgSO ₄ , filtered and evaporated to dryness to afford 60 g of crude product, which was dissolved in 250 ml of CH ₂ Cl ₂ . Then 30 g of silica was added to the solution. After stirring for 15 minutes, the silica was filtered off and rinsed twice with CH ₂ Cl ₂ (250 ml and 100 ml). The filtrate was concentrated to dryness and dried at 20 ° C. under 1 mbar to give 54.8 g of the expected product 17 (white solid).

Step 2: (3R, 4R, 5S) -4-hydroxy-5-[(1R) -1-hydroxyprop-2-en-1-yl] -3-methoxydihydrofuran-2 (3H) Preparation of on-ion ( 18 )

10 ml of TFA was added dropwise to a 100 ml round bottom flask containing 17 1.0 g (4.38 mmol), 10 ml of water and 14 ml of THF at 0 ° C. The medium was returned to AT and stirred overnight. The medium was then concentrated under reduced pressure at AT, 50 ml of water were added, the mixture was frozen and lyophilized. The lyophilisate was pasted in heptane in the presence of a minimum amount of methanol, and then the solvent was evaporated off. Expected product 18 778 mg (white solid) were obtained.

Step 3: (3R, 4R, 5S) -5-[(1R, 2E) -3-cyclopentyl-1-hydroxyprop-2-en-1-yl] -4-hydroxy-3-methoxydi Preparation of Hydrofuran-2 (3H) -one ( 19 )

18 100 mg (0.53 mmol), 4 ml CH ₂ Cl ₂ , 726 μl (5.3 mmol) of vinylcyclopentane, followed by 90.2 mg (106 μmol) of the second Grubbs catalyst were introduced into a 5 ml vial. The solution was microwave heated at 60 ° C. for 10 minutes. The solvent was then evaporated to dryness under reduced pressure, and the residue was then purified on a Biotage 12-M silica column (eluent: 40/60 Hept / EtOAc). Product 19 (76.3 mg, Rf = 0.35 under the elution conditions used) was obtained in the form of a brown solid.

Step 4: (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3, 4, 5-trihydroxy-2-methoxy-N-[(3S) -2-oxo-7-phenyl- 2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] hept-6-enamide Preparation of ( Ex5 )

19 100 mg (0.39 mmol), 14a 112.6 mg (0.39 mmol) and 162 mg (0.98 mmol) sodium 2-ethylhexanoate in 2.0 ml of THF were introduced into the Wheaton tube continuously under argon atmosphere with stirring. Stirring was maintained at AT for 24 h. The reaction medium was directly evaporated to dryness. The crude material was chromatographed on silica cartridge (12 g, eluent EtOAc). Expected product Ex5 92 mg (white solid) were obtained.

Ex6 : (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N-[(3S-1-methyl-2-oxo-2, 3,4,5-tetrahydro-1H-1-benzazin-3-yl] hept-6-enamide

Step 1: Preparation of tert-butyl [(3S) -1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl] carbamate ( 7a )

0.898 mg (22.44 mmol) of sodium hydride in a 60% suspension in oil was introduced under AT into an 500 ml round bottom flask with 260 ml of THF and 6.2 g (22.44 mmol) of 2a under stirring. The medium was stirred for 1 h, then 3.823 g (26.94 mmol) of methyl iodide were added. The medium is stirred overnight, 500 ml of EtOAc are added and the organic phase is washed twice with 500 ml of water. The organic phase was dried over MgSO ₄ , filtered and then evaporated to dryness. 6.85 g of crude product were obtained. After chromatography on a silica cartridge (250 g, eluent heptane / EtOAc to EtOAc gradient: 10 to 50%), 4.47 g of product 7a (white solid) was obtained.

Step 2: Preparation of (3S) -3-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazin-2-one hydrochloride ( 8a )

4.36 g (15.01 mmol) of 7a were dissolved in a 250 ml round bottom flask and 110 ml of a solution of hydrochloric acid (4 M) in dioxane were added. The mixture was stirred under argon at AT for 4 h. After evaporating off the solvent, the solid was digested with 25 ml of isopropyl ether and filter-dried on sintered glass. After drying, 3.1 g of amine 8a in the hydrochloride form was obtained, which was used directly in the next step.

Step 3: (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N-[(3S) -1-methyl-2-oxo- Preparation of 2,3,4,5-tetrahydro-1H-1- benzazin -3-yl] hept-6- enamide ( Ex6 )

19 100 mg (0.39 mmol), 8a 88.42 mg (0.39 mmol) and 162 mg (0.98 mmol) sodium 2-ethylhexanoate in 2.0 ml of THF were introduced into a Wheaton tube continuously under argon atmosphere with stirring. Stirring was maintained at AT for 24 h. The reaction medium was directly evaporated to dryness. Crude was chromatographed on silica cartridge (12 g, eluent EtOAc) and expected product Ex6 60 mg (white solid) were obtained.

Biological Activity of the Product Prepared:

In the present application, Caco2-TC7 (Papp single point = 48.10 ^-7 cm.sec ^-1 ) of the product of Example 4a is that of the product of Example 22a described in patent application WO 2006/056696 (Papp single point = 6.10 ^-7 cm.sec ^-1 ).

Antiproliferative activity of the products of the Examples of Table 1 was determined by measuring the proliferation inhibition rate of HCT116 cells. The cells are seeded in cell culture medium at a concentration of 10,000 cells per well in 0.17 ml of medium, 20 μl of test product at various concentrations and thymidine [methyl-14C] (100 μCi / ml-inactive 47.90 mCi / mmol; NEN Technologies) (NEN Technologies) Reference NEC568 Batch 3550-001) 10 μl was added and the cells were incubated at 37 ° C. and 5% CO ₂ .

Medium used for HCT 116 cell culture: DMEM medium, 2 mM L-glutamine, 200 IU / mL penicillin, 200 μg / ml streptomycin and 10% (V / V) fetal bovine serum (Life Technologies).

After 96 hours, the incorporation of ¹⁴ C-thymidine was counted with a 1450 Microbeta Wallac Trilux liquid scintillation counter. The resulting R is expressed in cpm (count per minute), first subtracting the cpm mean B of the cellless wells and then cpm value C of the wells of untreated cells containing 20 μl of product dilution medium containing 1% ethanol. Divided into growth inhibition rate GI% (GI% = (R-B) x100 / C%).

Using equation 205 of the XLFit software (IDBS Company, UK), the Marquardt algorithm (Donald W. MARQUARDT, J. Soc.industry.appl, vol 11, No. 2, June, 1963) IC ₅₀ values were calculated by non-linear regression analysis used.

The products in Table 1 generally have IC ₅₀ of less than 30 μM, preferably less than 100 nM for HCT116 cells. For example, the product of Example 1 has an IC ₅₀ of 14 nM and the product of Example 3 has an IC ₅₀ of 58 nM. Example product 2 has an IC ₅₀ of 15 nM, the product of Example 3a has a IC ₅₀ of 32 nM, the product of Example 4 has an IC ₅₀ of 75 nM, the product of Example 4a was 14 nM Has an IC ₅₀ .

Claims (26)

The product of formula (I) <Formula I>

In the formula: a) R ₁ is independently (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyl (C ₁ -C ₁₂ ) alkyl, cycloalkyl (C ₂ -C ₁₂ ) alkenyl, cycloalkyl (C ₂ -C ₁₂ ) alkynyl, heterocyclyl (C ₁ -C ₁₂ ) alkyl, heterocyclyl (C ₂ -C ₁₂ ) alkenyl, heterocyclyl (C ₂ -C ₁₂ ) alkynyl, aryl (C ₁ -C ₁₂ ) alkyl, aryl (C ₂ -C ₁₂ ) alkenyl, aryl (C ₂ -C ₁₂ ) Alkynyl, heteroaryl (C ₁ -C ₁₂ ) alkyl, heteroaryl (C ₂ -C ₁₂ ) alkenyl, heteroaryl (C ₂ -C ₁₂ ) alkynyl, each of R ₁ aryl The group is optionally substituted with one or more halogens; b) R ₂ is (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkylthio ( C ₁ -C ₆ ) alkyl, di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, aryloxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C _1- C ₆ ) alkyl; c) R ₃ is selected from the group consisting of H, COO (R ₅ ), CONH (R ₅ ), CO (R ₅ ), O (R ₅ ) and R ₅ ; d) R ₄ is independently H, F, Cl, Br, N (R ₅ ) ₂ , NO ₂ , CN, COO (R ₅ ), CON (R ₅ ) ₂ , NHCO (R ₅ ), NHCOO (R ₅ ), OCONH (R ₅ ), O (R ₅ ) and R ₅ , or two substituents R ₄ attached to two adjacent carbons of phenyl together are cycloalkyl, heterocyclyl, aryl or heteroaryl Form a ring selected from which are optionally substituted with one or more R ₄ ; e) m has a value of 0, 1, 2, 3 or 4; f) R ₅ is independently a pair of non-bonding electrons, H, (C ₁ -C ₁₂ ) alkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, halo (C ₁ -C ₁₂ ) alkyl, aryl (C ₁ -C ₁₂ ) alkyl, heteroaryl (C ₁ -C ₁₂ ) alkyl, heteroarylaryl (C ₁ -C ₁₂ ) alkyl, aryl, heteroaryl and cycloalkyl, Wherein each R ₅ is OH, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, aryl (C ₁ -C ₄ ) alkyl, aryl, heteroaryl (C ₁ -C ₄ ) alkyl , Heteroaryl, -N (CH ₃ ) ₂ , -NH ₂ , CONH ₂ ,

Optionally substituted with one or more substituents selected from, each Rz is, independently, a group consisting of H, COO (R ₅ ), CONH (R ₅ ), CON (R ₅ ) ₂ , CO (R ₅ ) and R ₅ are selected from wherein each R ₅ is independently (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkyl, aryl (C ₁ -C ₄₎ alkyl and heteroaryl (C ₁ -C ₄ to Alkyl, wherein each R ₅ is OH, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, aryl (C ₁ -C ₄ ) alkyl, aryl, heteroaryl (C Optionally substituted with a substituent selected from ₁ -C ₄ ) alkyl and heteroaryl; Provided that when R ₁ is (E) -CH = CH-C (CH ₃ ) ₃ , R ₂ is methyl and R ₃ is H, m is not zero. The compound of claim 1, wherein R ₁ is selected from -C (R ₆ ) = C (R ₇ ) (R ₈ ), wherein R ₆ , R ₇ and R ₈ are independently H, (C ₁ -C ₆ ) A product selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. The compound of claim 2, wherein R ₁ represents (E) —CH═CH—CH (CH ₃ ) (C ₂ H ₅ ), (E) —CH═CH—CH (CH ₃ ) ₂ and (E) —CH = Product selected from CH-C (CH ₃ ) ₃ . The compound of claim 2, wherein R ₁ is (E) —C (CH ₃ ) = CH—CH (CH ₃ ) (C ₂ H ₅ ), (E) —C (CH ₃ ) = CH—CH (CH ₃ ) ₂ and (E) -C (CH ₃ ) = CH-C (CH ₃ ) ₃ . The product according to any one of claims 1 to 4, wherein R ₂ is methyl. The product according to claim 1, wherein R ₃ is independently selected from a methyl group or a (3,5-difluorophenyl) methyl group. 6. The product according to claim 1, wherein R ₃ is H. 7. 8. The product according to claim 1, wherein R ₄ is independently selected from F, Cl, Br, phenyl and pyridinyl. 8. The product according to claim 1, wherein m is 0. 9. The method according to any one of claims 1 to 9, N- [1- (3,5-difluorobenzyl) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E)-( 2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide; N- [1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl]-((E)-(2R, 3R, 4S, 5R)- 3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide; N-((3S) -7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S , 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide; N-((3S) -7-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazin-3-yl)-(E)-(2R, 3R, 4S, 5R) -3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide. The method according to any one of claims 1 to 9, (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N-[(3S) -1-methyl-2-oxo-2,3 , 4,5-tetrahydro-1H-1-benzazin-3-yl] hept-6-enamide; (2R, 3R, 4S, 5R, 6E) -7-cyclopentyl-3,4,5-trihydroxy-2-methoxy-N-[(3S) -2-oxo-7-phenyl-2,3 , 4,5-tetrahydro-1H-1-benzazin-3-yl] hept-6-enamide. The method according to any one of claims 1 to 11, a) non-chiral form, or b) racemic form, or c) a form rich in one stereoisomer, or d) is in a form rich in one enantiomer; Product characterized in that it is optionally chlorided. 13. A product according to any one of claims 1 to 12, or an addition salt with a pharmaceutically acceptable acid of said product, or alternatively a hydrate or solvate of the product of formula (I). medicine. A pharmaceutical comprising a product of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. Composition. Use of a product according to any one of claims 1 to 12 for the manufacture of a medicament which can be used for preventing or treating a pathological condition. Use according to claim 15, wherein the pathological condition is cancer. 13. A process for preparing the product of formula I or I 'according to any one of claims 1 to 12, characterized in that the product of formula I or I' is obtained by hydrolysis of the product of formula II. <Formula II>

Wherein R ₁ , R ₂ , R ₃ , R ₄ and m are as defined above. The process according to claim 17, wherein the product of formula III is reacted with a product of formula IV to obtain the product of formula II. Method of preparation of the product. <Formula III>

Wherein R ₃ , R ₄ and m are as defined above. <Formula IV>

Wherein R ₁ and R ₂ are as defined above. A product of formula (I) or (I ') according to any one of claims 1 to 12, characterized by reacting the product of formula (III) with the product of formula (V) Way. <Formula III>

Wherein R ₃ , R ₄ and m are as defined above. <Formula V>

Wherein R ₁ and R ₂ are as defined above. The process for preparing the product of formula I or I 'according to any one of claims 1 to 11, characterized in that the product of formula V is hydrolyzed to obtain the product of formula V. . <Formula IV>

Wherein R ₁ and R ₂ are as defined above. <Formula V>

Wherein R ₁ and R ₂ are as defined above. The method according to any one of claims 1 to 12, wherein the product of formula VII is hydrolyzed to obtain a product of formula VI, which is metathesized to obtain a product of formula V. Process for the preparation of the product of formula (I) or (I ') according to the invention. <Formula VII>

Wherein R ₂ is as defined above. <Formula VI>

Wherein R ₂ is as defined above. <Formula V>

Wherein R ₁ is —CH═CH—R ′ and R ′ ₁ is a (C ₁ -C ₆ ) alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group. The process according to claim 21, wherein the product of formula VII is obtained by double dehydration of the product of formula VIII. . <Formula VII>

Wherein R ₂ is as defined above. <Formula VIII>

Wherein R ₂ is as defined above. The compound of any one of claims 17-22, except that R ₁ is (E) —CH═CH—C (CH ₃ ) ₃ , R ₂ is methyl, R ₃ is H, and m is 0. Products of formulas I 'and II as defined. R ₃ is H, methyl or (3,5-difluorophenyl) methyl, and R ₄ is bromine atom or phenyl or m is 0 except that R ₃ is H and m has a value of 0 The product of formula III, characterized in that The product of formulas IV and V, wherein R ₂ is methyl and R ₁ is-(E) -CH = CH-C ₅ H ₉ . The product of formula VI, wherein R ₂ is methyl.